The invention relates to the field of therapeutic compounds, their uses, methods of use and compositions comprising them. This invention also relates to the treatment of diseases resulting from accumulation of P-glycoprotein substrates. This invention also relates to the treatment of diseases associated with cellular migration and/or angiogenesis and neurological diseases.
ABC (ATP-Binding Cassette) transporters superfamily members are expressed on most mammalian tissues with excretory and/or barrier function. These transporters are involved in unidirectional substrate translocation and use ATP as the energy source to activate the extrusion process. ABC transporters appear to have developed as a mechanism to protect the body from harmful substances.
P-glycoprotein (P-gp) is an ABC transporter, product of the MDR1 gene, found in the liver, gut, gonads, kidneys, biliary system, brain, and other organs. P-glycoprotein is an efflux pump protecting the structural and functional integrity of the organs and tissues on which it is expressed. P-glycoprotein is localized at the plasma membrane, more specifically in microdomains enriched in cholesterol called caveolae. Caveolae may act as signaling platforms and can be identified by the presence of specific markers such as caveolin-1, -2, and -3. This particular localization seems to be important for P-gp ATPase and transport activities. Recent work suggests that two P-gp populations co-exist in the plasma membrane surrounded by different cholesterol concentration in the P-gp closed microenvironment (Barakat et al., Biochem. J. 388:563-571, 2005). P-glycoprotein is associated with multi-drug resistance. Indeed, P-gp interacts with a wide variety of anti-cancer drugs leading to a decrease in their intracellular concentrations ultimately leading to failure of chemotherapy. P-glycoproteins have also been linked to neurological diseases. Indeed, neurological disorders including but not limited to epilepsy, Alzheimer's disease and Huntington's disease are associated with overexpression of ABC efflux transporters or substrates. Apart from their efflux transport activity, P-glycoproteins are also known to play a role in cellular migration and angiogenesis.
Given the involvement of P-gp substrates in disease, there is a need to develop therapeutic approaches aimed at regulating P-gp function, which can reduce the accumulation of P-gp substrates, can inhibit cellular migration or angiogenesis, or can treat neurological disorders and other diseases.